CD44, a therapeutic target for metastasising tumours

https://doi.org/10.1016/j.ejca.2010.02.024Get rights and content

Abstract

Members of the CD44 family of transmembrane glycoproteins, in particular CD44v6 isoforms, were shown to be metastatic determinants of rat pancreatic tumour cells back in the early 1990s. Furthermore, the expression of several CD44 proteins correlates with aggressive stages of various human cancers. Because of the frequent and homogeneous expression of CD44v6 isoforms in squamous cell carcinoma, antibodies recognising these proteins were used in clinical trials for patients suffering from head and neck squamous cell carcinoma (HNSCC). Although the phase I clinical trials looked promising, the studies were abruptly ended after the death of a patient. Despite the termination of the trials, CD44 certainly remains a valid target for anti-cancer therapy. In this review, alternative strategies targeting CD44 functions are presented. These functions include the binding to hyaluronan (HA), the collaboration with osteopontin and the contribution of CD44 isoforms to receptor tyrosine kinase (RTKs) activation. These new attempts led to the development of peptides that interfere for example with HA binding and that might be used to induce apoptosis in mammary carcinoma or to prevent homing of leukaemia stem cells. Other peptides block RTK activation and thereby inhibit tumour angiogenesis and metastatic spread.

Section snippets

The cell adhesion protein family CD44

Together with the selectins, the integrins and the cadherins, CD44 transmembrane glycoproteins form part of the huge family of cell adhesion molecules (CAMs). The CAMs control cell behaviour by mediating contact between cells or between cells and the extracellular matrix and are therefore essential for maintaining tissue integrity. Because of these important functions they are prone to be involved in pathological conditions including tumour progression and metastasis. One of the most striking

Importance of CD44 variants in metastasis

CD44 proteins regulate growth, survival, differentiation and migration and are thereby prone to be involved in tumour progression and metastasis. The first major finding involving CD44 in the metastatic process was the identification of a CD44 variant isoform containing the exons v4–v7 in a highly metastasizing rat pancreatic carcinoma cell line (BSp73ASML). Transfection of this specific variant into the related BSp73AS cells that do not metastasize conferred the metastatic potential to these

Influence of HA binding on metastasis

As mentioned in the introduction, the main property ascribed to CD44 is its ability to bind HA. For this reason, this was the first function of CD44 that was believed to be important for the metastatic process. However, despite intensive research, the data are still contradictory. One attempt to elucidate the role of HA binding to CD44 in tumour progression was made with the pancreatic carcinoma cells BSp73AS transfected with the CD44v4–v7 isoforms that conferred the metastatic potential.7

Outlook

There is ample evidence that CD44 isoforms and specifically the CD44v6 isoforms are involved in the metastatic process. Several studies show that the function of CD44 as an HA binding protein is crucial for tumour progression, although this seems not to be a common feature for all tumours. Furthermore, the co-receptor function of CD44v6 for c-Met and also for VEGFR-2 might be crucial for the establishment of primary tumours as well as for metastasis, at least in pancreatic carcinoma. For these

Conflict of interest statement

None declared.

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